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The Serotonin-1A Receptor in Anxiety Disorders

      The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders.

      Key Words

      Brain serotonin (5-HT) plays a major role in a number of physiological processes and pathological conditions. Serotonin neurotransmission is involved in the regulation of mood, impulse control, sleep, vigilance, eating, libido, and cognitive functions, such as memory and learning. In addition, serotonin is important in the modulation of anxiety and fear, as well as impulsiveness in suicidal and other violent acts (
      • Arango V.
      • Underwood M.D.
      • Boldrini M.
      • Tamir H.
      • Kassir S.A.
      • Hsiung S.
      • et al.
      Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims.
      ,
      • Lemonde S.
      • Turecki G.
      • Bakish D.
      • Du L.
      • Hrdina P.D.
      • Bown C.D.
      • et al.
      Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide.
      ). These effects are mediated by at least 14 different 5-HT receptors (
      • Barnes N.M.
      • Sharp T.
      A review of central 5-HT receptors and their function.
      ). Among them, the serotonin-1A (5-HT1A) receptor in particular is thought to play an important role in the etiology of anxiety disorders, supported by the fact that partial 5-HT1A receptor agonists are anxiolytics (
      • Goldberg H.L.
      • Finnerty R.J.
      The comparative efficacy of buspirone and diazepam in the treatment of anxiety.
      ).
      Nonpsychotic and nonorganic anxiety is part of the following disorders: phobic anxiety disorders, general anxiety disorder (GAD), panic disorder (PD), obsessive-compulsive disorder (OCD), reaction to severe stress as acute stress reaction, and posttraumatic stress disorder (PTSD). Pathological harm avoidance, induced by conflict and fear, is a dimension of anxiety-related responses and may also be associated with increased 5-HT functional activity (
      • Cloninger C.R.
      A systematic method for clinical description and classification of personality variants A proposal.
      ,
      • Bailer U.F.
      • Price J.C.
      • Meltzer C.C.
      • Mathis C.A.
      • Frank G.K.
      • Weissfeld L.
      • et al.
      Altered 5-HT(2A) receptor binding after recovery from bulimia-type anorexia nervosa: Relationships to harm avoidance and drive for thinness.
      ,
      • Bailer U.F.
      • Frank G.K.
      • Henry S.E.
      • Price J.C.
      • Meltzer C.C.
      • Mathis C.A.
      • et al.
      Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa.
      ). All of these disorders have common behavioral and physiological characteristics that respond to similar pharmacological treatment. Selective serotonin reuptake inhibitors (SSRIs) have become the first-line treatment for anxiety disorders. They act by selectively blocking the reuptake of 5-HT following its release from neurons, thereby changing 5-HT neurotransmission in the brain, including binding on the 5-HT1A receptor (
      • Spindelegger C.
      • Lanzenberger R.
      • Wadsak W.
      • Mien L.K.
      • Stein P.
      • Mitterhauser M.
      • et al.
      Influence of escitalopram treatment on 5-HT(1A) receptor binding in limbic regions in patients with anxiety disorders.
      ,
      • Sibon I.
      • Benkelfat C.
      • Gravel P.
      • Aznavour N.
      • Costes N.
      • Mzengeza S.
      • et al.
      Decreased [18F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: A positron-emission tomography study in healthy volunteers.
      ).
      Due to the high density of the 5-HT1A receptor subtype in several cortical and subcortical areas, this receptor is considered the major inhibitory serotonergic receptor (
      • Varnas K.
      • Halldin C.
      • Hall H.
      Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain.
      ). See Figure 1 for the distribution of 5-HT1A receptors in the human brain. The 5-HT1A receptor is expressed in high concentration in limbic, temporal, and prefrontal cortices, while having low density in the primary sensory areas. It is not yet certain how 5-HT1A alterations in different human brain areas are specifically associated with dysfunctions in anxiety processing. However, the topology of 5-HT1A alterations is a relevant factor. Given its broad distribution within the cortex, it is important to consider that 5-HT1A plays a role not only in anxiety and affective disorders, but also in the regulation of a variety of physiological states and behaviors, including fear, aggression, and impulsivity, as recently demonstrated by Witte et al. (
      • Witte A.V.
      • Floel A.
      • Stein P.
      • Savli M.
      • Mien L.K.
      • Wadsak W.
      • et al.
      Aggression is related to frontal serotonin-1A receptor distribution as revealed by PET in healthy subjects.
      ). Several human positron emission tomography (PET) studies showed that the lower tracer binding of the receptor observed in patients with psychiatric disorders, when compared with control subjects, was limited to distinct regions of the brain (
      • Drevets W.C.
      • Thase M.E.
      • Moses-Kolko E.L.
      • Price J.
      • Frank E.
      • Kupfer D.J.
      • et al.
      Serotonin-1A receptor imaging in recurrent depression: Replication and literature review.
      ). Brain 5-HT1A receptors are located both presynaptically and postsynaptically. Presynaptic 5-HT1A receptors are present on serotonergic neurons in the dorsal and medial raphe nuclei and act as somatodendritic autoreceptors. The activation of these receptors by 5-HT causes a reduction in the firing rate of the serotonergic neurons and suppression of 5-HT synthesis, 5-HT turnover, and 5-HT release in projection areas. Postsynaptic 5-HT1A receptors are mainly located on glutamatergic and GABAergic (gamma-aminobutyric acid) pyramidal neurons in limbic regions and in the frontal and entorhinal cortices (
      • Artigas F.
      • Adell A.
      • Celada P.
      Pindolol augmentation of antidepressant response.
      ,
      • Palchaudhuri M.
      • Flugge G.
      5-HT1A receptor expression in pyramidal neurons of cortical and limbic brain regions.
      ,
      • Azmitia E.C.
      • Gannon P.J.
      • Kheck N.M.
      • Whitaker-Azmitia P.M.
      Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells.
      ). They modulate serotonergic sensitivity and are involved in emotional and cognitive processes (
      • Varnas K.
      • Halldin C.
      • Hall H.
      Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain.
      ,
      • Hall H.
      • Lundkvist C.
      • Halldin C.
      • Farde L.
      • Pike V.W.
      • McCarron J.A.
      • et al.
      Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635.
      ).
      Figure thumbnail gr1
      Figure 1Serotonin-1A receptor distribution in the healthy human brain. The color table indicates the 5-HT1A receptor binding potential superimposed on magnetic resonance images (triplanar sections with coronal, sagittal, and axial views; brain surface). The binding was measured using positron emission tomography and the highly selective and specific radioligand [carbonyl-11C]WAY-100635. Red crosshairs indicate the raphe nuclei region expressing presynaptic 5-HT1A autoreceptors on serotonergic neurons. The postsynaptic 5-HT1A receptors in cortical regions are mainly expressed on glutamatergic and GABAergic pyramidal neurons. High 5-HT1A receptor densities (red) can be found in limbic areas including the hippocampus and cingulate cortex and in prefrontal and temporal cortices. Low densities are expressed in the primary visual cortex and the primary motor cortex. 5-HT1A, serotonin-1A.
      This overview aims to present the most important literature currently available on clinical and preclinical findings demonstrating the pivotal role of the 5-HT1A receptor in anxiety disorders.

      Results in Animal Studies

      Previous results in rats (
      • Overstreet D.H.
      • Commissaris R.C.
      • De La Garza 2nd, R.
      • File S.E.
      • Knapp D.J.
      • Seiden L.S.
      Involvement of 5-HT1A receptors in animal tests of anxiety and depression: Evidence from genetic models.
      ,
      • Knapp D.J.
      • Overstreet D.H.
      • Crews F.T.
      Brain 5-HT1A receptor autoradiography and hypothermic responses in rats bred for differences in 8-OH-DPAT sensitivity.
      ), knockout mice (
      • Toth M.
      5-HT1A receptor knockout mouse as a genetic model of anxiety.
      ), and nonhuman primates (
      • Bethea C.L.
      • Pau F.K.
      • Fox S.
      • Hess D.L.
      • Berga S.L.
      • Cameron J.L.
      Sensitivity to stress-induced reproductive dysfunction linked to activity of the serotonin system.
      ) showed the key role of the 5-HT1A receptor in the modulation of behavioral correlates, anxiety and fear, that may have counterparts to anxiety and fear in humans (Table 1).
      Table 15-HT1A and Transgenic Mice as Genetic Models of Anxiety Disorders
      Behavioral FeaturesKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicRescue-Turned Off in the AdultRescue-Turned Off During DevelopmentReferences
      Anxiety-Related Responses=
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ,
      • Zhuang X.
      • Gross C.
      • Santarelli L.
      • Compan V.
      • Trillat A.C.
      • Hen R.
      Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.
      Harm Avoidance=
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ,
      • Zhuang X.
      • Gross C.
      • Santarelli L.
      • Compan V.
      • Trillat A.C.
      • Hen R.
      Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.
      Aggression==n.t.n.t.
      • Zhuang X.
      • Gross C.
      • Santarelli L.
      • Compan V.
      • Trillat A.C.
      • Hen R.
      Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.
      ,
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      Fear Conditioningn.t.n.t.n.t.n.t.
      • Klemenhagen K.C.
      • Gordon J.A.
      • David D.J.
      • Hen R.
      • Gross C.T.
      Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.
      Exploratory Activity=
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ,
      • Zhuang X.
      • Gross C.
      • Santarelli L.
      • Compan V.
      • Trillat A.C.
      • Hen R.
      Altered emotional states in knockout mice lacking 5-HT1A or 5-HT1B receptors.
      Learning Deficitn.t.n.t.n.t.n.t.
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      Freezing Response After Shockn.t.n.t.n.t.n.t.
      • Klemenhagen K.C.
      • Gordon J.A.
      • David D.J.
      • Hen R.
      • Gross C.T.
      Increased fear response to contextual cues in mice lacking the 5-HT1A receptor.
      5-HT1A, serotonin-1A; ↑, significant increase; ↓, significant decrease; =, changes were not significant; n.t., not tested.
      In our overview, we focus on transgenic and knockout mice models of the 5-HT1A receptor, which represent a genetic model of anxiety and are useful in explaining pathogenetic pathways leading to this disorder (
      • Lesch K.P.
      Mouse anxiety: The power of knockout.
      ). A significant increase in the anxiety level and anxious behavior is present not only in homozygote but also in heterozygote 5-HT1A receptor knockout mice, indicating that a partial receptor deficit is sufficient to elicit the phenotype. Therefore, receptor downregulation may be an important risk factor in psychiatric disorders. Table 1, Table 2, Table 3 summarize preclinical results described in detail below.
      Table 2Behavioral Conflict Tests on 5-HT1A Knockout and Transgenic Mice
      Conflict Tests, Anxiety ParadigmsKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicRescue-Turned Off in the AdultRescue-Turned Off During DevelopmentReferences
      Home Cage Activity==n.t.n.t.
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      Light-Dark Testn.t.n.t.n.t.n.t.
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      Open Field==
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      Elevated-Plus Maze=
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      Novel Object=n.t.n.t.n.t.
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      Tail Suspensionn.t.n.t.n.t.
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      Forced Swim Testn.t.n.t.n.t.
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      Morris Water Mazen.t.n.t.n.t.n.t.
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      Novelty Suppressed Feedingn.t.n.t.=
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      Novel Environmentn.t.n.t.n.t.n.t.
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      Freezing Responsen.t.n.t.n.t.n.t.
      • Sarnyai Z.
      • Sibille E.L.
      • Pavlides C.
      • Fenster R.J.
      • McEwen B.S.
      • Toth M.
      Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin (1A) receptors.
      5-HT1A, serotonin-1A; ↑, significant increase; ↓, significant decrease; =, changes were not significant; n.t., not tested.
      Table 3Physiological and Autonomic Changes in 5-HT1A Knockout and Transgenic Mice
      Physiological Features, Autonomic ChangesKnockout 5-HT1A−/−Heterozygote 5-HT1A+/−Overexpression 5-HT1A TransgenicReferences
      Heart Rate==n.t.
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      Basal Body Temperature==↓ (male)
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      ,
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      Stressed-Induced Tachycardia=n.t.
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      Stressed-Induced Hyperthermia=n.t.
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      ,
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ,
      • Olivier B.
      • Zethof T.
      • Pattij T.
      • van Boogaert M.
      • van Oorschot R.
      • Leahy C.
      • et al.
      Stress-induced hyperthermia and anxiety: Pharmacological validation.
      Stress Responsesn.t.
      • Olivier B.
      • Zethof T.
      • Pattij T.
      • van Boogaert M.
      • van Oorschot R.
      • Leahy C.
      • et al.
      Stress-induced hyperthermia and anxiety: Pharmacological validation.
      ,
      • Olivier B.
      • Zethof T.
      • Pattij T.
      • van Boogaert M.
      • van Oorschot R.
      • Leahy C.
      • et al.
      Stress-induced hyperthermia and anxiety: Pharmacological validation.
      ,
      • Groenink L.
      • Van der Gugten J.
      • Verdouw P.M.
      • Maes R.A.
      • Olivier B.
      The anxiolytic effects of flesinoxan, a 5-HT1A receptor agonist, are not related to its neuroendocrine effects.
      ,
      • Lopez J.F.
      • Chalmers D.T.
      • Little K.Y.
      • Watson S.J.
      A.E. Bennett Research Award Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression.
      ACTH, Prolactin, Corticosterone, Adrenaline Levelsn.t.n.t.
      • Parsons L.H.
      • Kerr T.M.
      • Tecott L.H.
      5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.
      Glucose Leveln.t.n.t.
      • Parsons L.H.
      • Kerr T.M.
      • Tecott L.H.
      5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.
      Serotonin Leveln.t.n.t.
      • Parsons L.H.
      • Kerr T.M.
      • Tecott L.H.
      5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.
      5-HT1A, serotonin-1A; ACTH, adrenocorticotropic hormone; ↑, significant increase; ↓, significant decrease; =, changes were not significant; n.t., not tested.

       Behavioral Features in 5-HT1A Receptor Knockout Mice

      Three knockout lines were generated from different genetic backgrounds and tested under similar conditions to evaluate fear, avoidance, conflict, and stress responsiveness (
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ). Mice with the genetic deletion of the 5-HT1A receptor were shown to be more fearful in a number of behavioral conflict tests.

       Transgenic Mice Models

      As the 5-HT1A receptor is expressed postsynaptically on glutamatergic and GABAergic neurons and presynaptically on serotonergic neurons in the raphe nuclei, it is of major interest to know whether a presynaptic or postsynaptic receptor pool is required to maintain a normal level of fear and anxiety in mice.
      Gross et al. (
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ) created a mouse with a double transgenic line, otherwise known as the “rescue” line. This mouse exhibits postsynaptic 5-HT1A receptors that approximately imitate the wild-type receptor pattern in the forebrain; however, presynaptic receptors are not expressed in the raphe nuclei of the brainstem.
      Rescue mice demonstrate wild-type levels of anxiety, showing a reversal of the anxiety phenotype of knockout mice. This means that 5-HT1A receptors in the forebrain are able to restore normal anxiety behavior in knockout background, suggesting an important role for forebrain receptors in regulating anxiety behavior in wild-type mice. Gross et al. (
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ) studied the conditional nature of the receptor in rescue mice to assess the effect of 5-HT1A receptors during development and adulthood in the rescue phenotype. Test results indicated that deletion of the 5-HT1A receptor in mice produces a robust anxiety-related phenotype and that this phenotype in 5-HT1A knockout mice is caused by the absence of the receptor at a critical period of postnatal development, whereas the knockout of 5-HT1A in adulthood does not affect anxiety. Even more significantly, these findings support the idea of a central role for serotonin in the early development of neurocircuits mediating emotion (
      • Ansorge M.S.
      • Morelli E.
      • Gingrich J.A.
      Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.
      ,
      • Ansorge M.S.
      • Zhou M.
      • Lira A.
      • Hen R.
      • Gingrich J.A.
      Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice.
      ).
      To further analyze the role of the 5-HT1A receptor in anxiety-like behavior, transgenic mice overexpressing this receptor subtype were generated (
      • Kusserow H.
      • Davies B.
      • Hortnagl H.
      • Voigt I.
      • Stroh T.
      • Bert B.
      • et al.
      Reduced anxiety-related behaviour in transgenic mice overexpressing serotonin 1A receptors.
      ). The expression of the 5-HT1A receptor protein was transiently increased during postnatal development. Interestingly, transgenic mice showed elevated serotonin values in the hippocampus and striatum.
      Several studies have shown that steroid hormones such as cortisol and estrogenes are potent modulators of 5-HT1A receptor expression (
      • Gross C.
      • Hen R.
      The developmental origins of anxiety.
      ). While maternal stress during pregnancy changes the hormonal condition of the fetus, maternal behavior during the early postnatal phase influences the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal axes of the progeny (
      • Francis D.D.
      • Meaney M.J.
      Maternal care and the development of stress responses.
      ,
      • Francis D.D.
      • Champagne F.A.
      • Liu D.
      • Meaney M.J.
      Maternal care, gene expression, and the development of individual differences in stress reactivity.
      ). Given the sensitive periods in the maturation of the serotonergic system, these environmental factors may have life-long effects on serotonergic neurotransmission and 5-HT1A receptor expression causing vulnerability to stress in adulthood. These critical findings should be integrated into future research on humans to investigate whether multifactorial disorders may result from variations in a small number of genes, with varying effects dependent on the exposure to environmental risk factors like malfunctions of the maternal stress systems during pregnancy or stressful life events in early childhood (
      • McEwen B.S.
      Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators.
      ,
      • Caspi A.
      • Sugden K.
      • Moffitt T.E.
      • Taylor A.
      • Craig I.W.
      • Harrington H.
      • et al.
      Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene.
      ). Also, the association of genetic liability with personality traits like neuroticism, which seem to increase the likelihood of the development of psychiatric disorders, should be considered (
      • Hettema J.M.
      • Prescott C.A.
      • Kendler K.S.
      Genetic and environmental sources of covariation between generalized anxiety disorder and neuroticism.
      ,
      • Bienvenu O.J.
      • Hettema J.M.
      • Neale M.C.
      • Prescott C.A.
      • Kendler K.S.
      Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia, agoraphobia, and animal phobia.
      ).

       Autonomic Changes in 5-HT1A Receptor Knockout Mice

      Autonomic manifestations of anxiety, such as increased blood pressure, heart rate, and elevated body temperature, are experienced by anxiety patients. These factors were measured in animal models to determine anxiety levels (
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      ,
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ,
      • Olivier B.
      • Zethof T.
      • Pattij T.
      • van Boogaert M.
      • van Oorschot R.
      • Leahy C.
      • et al.
      Stress-induced hyperthermia and anxiety: Pharmacological validation.
      ). Pattij et al. (
      • Pattij T.
      • Groenink L.
      • Hijzen T.H.
      • Oosting R.S.
      • Maes R.A.
      • van der Gugten J.
      • et al.
      Autonomic changes associated with enhanced anxiety in 5-HT(1A) receptor knockout mice.
      ) observed that in a novel environment, the heart rate of 5-HT1A receptor knockout mice was twice that of wild-type control animals. Body temperature also increased more significantly in knockout animals. Baseline values of heart rate and body temperature showed no differences between the groups.

       Stress Responsiveness and the Hypothalamic-Pituitary-Adrenal System

      Increased stress responsiveness was observed in knockout mice when compared with wild-type mice in forced swim tests and tail suspension tests. Knockout mice, when placed in water or suspended by the tail, show a stress-induced increase in mobility (
      • Heisler L.K.
      • Chu H.M.
      • Brennan T.J.
      • Danao J.A.
      • Bajwa P.
      • Parsons L.H.
      • et al.
      Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice.
      ,
      • Parks C.L.
      • Robinson P.S.
      • Sibille E.
      • Shenk T.
      • Toth M.
      Increased anxiety of mice lacking the serotonin1A receptor.
      ,
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ). When using aversive stimuli to induce freezing, higher rates of stress and anxiety were displayed by knockout mice (
      • Gross C.
      • Santarelli L.
      • Brunner D.
      • Zhuang X.
      • Hen R.
      Altered fear circuits in 5-HT(1A) receptor KO mice.
      ,
      • Groenink L.
      • Van der Gugten J.
      • Verdouw P.M.
      • Maes R.A.
      • Olivier B.
      The anxiolytic effects of flesinoxan, a 5-HT1A receptor agonist, are not related to its neuroendocrine effects.
      ).
      Stress and anxiety disorders are frequently accompanied by the activation of the HPA system. The release of corticosterone by the adrenal gland was shown partially reduced in 5-HT1A receptor knockout mice (
      • Gross C.
      • Santarelli L.
      • Brunner D.
      • Zhuang X.
      • Hen R.
      Altered fear circuits in 5-HT(1A) receptor KO mice.
      ,
      • Sibille E.
      • Pavlides C.
      • Benke D.
      • Toth M.
      Genetic inactivation of the serotonin (1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety.
      ). Both glucocorticoid administration and chronic stress have also been shown to result in downregulation of 5-HT1A receptor density and messenger RNA (mRNA) levels in the hippocampus (
      • Lopez J.F.
      • Chalmers D.T.
      • Little K.Y.
      • Watson S.J.
      A.E. Bennett Research Award Regulation of serotonin1A, glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression.
      ,
      • Wissink S.
      • Meijer O.
      • Pearce D.
      • van Der Burg B.
      • van Der Saag P.T.
      Regulation of the rat serotonin-1A receptor gene by corticosteroids.
      ), where 5-HT1A receptor expression is inhibited by corticosteroid receptor stimulation. In contrast, 5-HT1A receptors in the raphe nuclei seem unaffected by circulating corticosteroids (
      • Chalmers D.T.
      • Kwak S.P.
      • Mansour A.
      • Akil H.
      • Watson S.J.
      Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression.
      ).

       Pharmacological Effects on the 5-HT1A Receptor

      Pharmacological tests on knockout mice are a powerful tool in understanding both the consequences of the deletion of 5-HT1A receptors and the effects of pharmacological treatment on this receptor (Table 1 in Supplement 1). Anxiety disorders are commonly treated with benzodiazepines that bind to GABAA receptors. The anxiolytic activity of benzodiazepines is dependent on the genetic background of knockout mice. It was shown that 5-HT1A receptor knockout mice display benzodiazepine-resistant anxiety (
      • Sibille E.
      • Pavlides C.
      • Benke D.
      • Toth M.
      Genetic inactivation of the serotonin (1A) receptor in mice results in downregulation of major GABA(A) receptor alpha subunits, reduction of GABA(A) receptor binding, and benzodiazepine-resistant anxiety.
      ). In contrast to these mutants, receptor-deficient mice of the 129sv and C57B16 genetic backgrounds responded to benzodiazepines (
      • Olivier B.
      • Pattij T.
      • Wood S.J.
      • Oosting R.
      • Sarnyai Z.
      • Toth M.
      The 5-HT(1A) receptor knockout mouse and anxiety.
      ). This data clearly demonstrates that benzodiazepine resistance is mediated by an interaction between the 5-HT1A receptor and one or more unknown genes and their modification in the GABAA complex is independent of the anxiety phenotype.
      Serotonin-1A receptors modulate the anxiolytic effects of SSRIs. In several investigations, pharmacological blockades in 5-HT1A receptor knockout mice were introduced and the impact on regulation of synaptic serotonin was studied, showing knockout mice to have increased fluoxetine-induced dialysate serotonin content in various brain regions (
      • Parsons L.H.
      • Kerr T.M.
      • Tecott L.H.
      5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.
      ,
      • Knobelman D.A.
      • Hen R.
      • Lucki I.
      Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse.
      ). Knobelman et al. (
      • Knobelman D.A.
      • Hen R.
      • Lucki I.
      Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse.
      ) presented results, indicating the significant role of the receptor in regulating 5-HT1A receptor-mediated release in the striatum and other brain regions innervated by neurons of the medial raphe nucleus. Similarly, Parson et al. (
      • Parsons L.H.
      • Kerr T.M.
      • Tecott L.H.
      5-HT(1A) receptor mutant mice exhibit enhanced tonic, stress-induced and fluoxetine-induced serotonergic neurotransmission.
      ) described a larger disinhibition of serotonin release in the frontal cortex than in the ventral hippocampus in knockout mice following treatment with fluoxetine.
      Pindolol is a β1–2 adrenergic receptor antagonist with a putative antagonistic action on 5-HT1A receptors and a greater occupation at somatodendritic 5-HT1A receptors than at postsynaptic receptors. While the clinical benefits of SSRIs are only evident after 4 to 6 weeks of treatment, pindolol seems to speed up this process. This effect may be mediated by somatodendritic 5-HT1A receptors. Guilloux et al. (
      • Guilloux J.P.
      • David D.J.
      • Guiard B.P.
      • Chenu F.
      • Reperant C.
      • Toth M.
      • et al.
      Blockade of 5-HT1A receptors by (+/−)-pindolol potentiates cortical 5-HT outflow, but not antidepressant-like activity of paroxetine: Microdialysis and behavioral approaches in 5-HT1A receptor knockout mice.
      ) studied the mechanism of pindolol and the antidepressant effect of a combination with paroxetine in 5-HT1A knockout mice. They found no effect on 5-HT1A autoreceptors. The blockade of paroxetine-induced antidepressant- and anxiolytic-like effects may be strongly associated with its binding to other neurotransmitter receptors.
      The effects of selective 5-HT1A receptor agonists and partial agonists were investigated in detail in rodents (
      • Jolas T.
      • Schreiber R.
      • Laporte A.M.
      • Chastanet M.
      • De Vry J.
      • Glaser T.
      • et al.
      Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat?.
      ). They cause a dose-dependent anxiolytic effect that correlates with the inhibition of serotonergic neuron firing, the decrease of 5-HT release, and the reduction of 5-HT signaling at postsynaptic target receptors. Blocking of the negative feedback by selective 5-HT1A receptor antagonists, such as WAY-100635, raises the firing level of the serotonergic neurons but has no obvious effects on 5-HT neurotransmission or behavior (
      • Olivier B.
      • Soudijn W.
      • van Wijngaarden I.
      The 5-HT1A receptor and its ligands: Structure and function.
      ), while the combination with SSRIs augments the rise in serotonin levels in terminal regions. The activation of presynaptic 5-HT1A receptors provides the brain with an autoinhibitory feedback system controlling serotonin neurotransmission. Increased anxiety-related behavior may be associated with increased serotonin, resulting from a dysregulated negative feedback function in 5-HT1A autoreceptors (
      • Lesch K.P.
      • Mossner R.
      Knockout corner: 5-HT(1A) receptor inactivation: Anxiety or depression as a murine experience.
      ). This mechanism is supported by recent theoretical models of fear and anxiety, primarily based on pharmacological data. The long-term reduction in serotonergic impulse flow to septohippocampal and other limbic and cortical areas involved in the control of anxiety may explain the anxiolytic effects of ligands with selective affinity for the 5-HT1A receptor in animal models of anxiety-related behavior. This is based on evidence that 5-HT1A agonists (8-OH-DPAT) and antagonists (WAY-100635) have anxiolytic or anxiogenic effects, respectively (
      • Collinson N.
      • Dawson G.R.
      On the elevated plus-maze the anxiolytic-like effects of the 5-HT(1A) agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT(1A) partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635.
      ). The effects of 5-HT1A agonists injected centrally vary according to brain regions. Injections into areas such as the hippocampus and amygdala produce anxiogenic effects; however, when 5-HT1A agonists are injected into the dorsal or median raphe nuclei, anxiolytic effects can be observed. This evidence suggests that the postsynaptic 5-HT1A receptors and the 5-HT1A autoreceptors have opposite effects in the regulation of anxious behavior. Blier et al. (
      • Blier P.
      • Ward N.M.
      Is there a role for 5-HT1A agonists in the treatment of depression?.
      ) suggested that therapeutic effects of antidepressants are the result of 5-HT1A autoreceptor downregulation during chronic treatment without an alteration in the postsynaptic 5-HT1A receptors. Consequently, the stimulation of postsynaptic 5-HT1A receptors seems to be axiogenic, while the activation of 5-HT1A autoreceptors may induce anxiolytic effects via suppression of serotonergic neuronal firing. This, in turn, results in attenuated serotonin release. To confirm this hypothesis in humans, further knowledge of the status of the 5-HT1A receptors must be gained. Further details can be found in Supplement 1.

      Results in Human Studies

       Pharmacological Effects on the 5-HT1A Receptor in Anxiety Disorders

      The efficacy of medications that increase the synaptic availability of serotonin has been shown consistently in clinical studies (
      • Bandelow B.
      • Zohar J.
      • Hollander E.
      • Kasper S.
      • Möller H.J.
      World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders—first revision.
      ). Selective serotonin reuptake inhibitors may increase anxiety during the initial phase of treatment, a phenomenon that indicates the possible oversensitivity of serotonin postsynaptic receptors (
      • Coplan J.D.
      • Gorman J.M.
      • Klein D.F.
      Serotonin related functions in panic-anxiety: A critical overview.
      ).
      Neuropharmacological challenge studies with ipsapirone (a selective 5-HT1A receptor agonist) have been conducted to evaluate 5-HT1A receptor-related functions in patients with various affective and anxiety disorders (
      • Broocks A.
      • Meyer T.
      • Opitz M.
      • Bartmann U.
      • Hillmer-Vogel U.
      • George A.
      • et al.
      5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo.
      ,
      • Broocks A.
      • Meyer T.
      • Gleiter C.H.
      • Hillmer-Vogel U.
      • George A.
      • Bartmann U.
      • et al.
      Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects.
      ,
      • Kahn R.S.
      • Trestman R.
      • Lawlor B.A.
      • Gabriel S.
      • Davidson M.
      • Siever L.
      Effects of ipsapirone in healthy subjects: A dose–response study.
      ,
      • Lerer B.
      • Gelfin Y.
      • Gorfine M.
      • Allolio B.
      • Lesch K.P.
      • Newman M.E.
      5-HT1A receptor function in normal subjects on clinical doses of fluoxetine: Blunted temperature and hormone responses to ipsapirone challenge.
      ,
      • Lesch K.P.
      • Rupprecht R.
      • Poten B.
      • Muller U.
      • Sohnle K.
      • Fritze J.
      • et al.
      Endocrine responses to 5-hydroxytryptamine-1A receptor activation by ipsapirone in humans.
      ). The 5-HT1A challenge studies by Broocks et al. (
      • Broocks A.
      • Meyer T.
      • Opitz M.
      • Bartmann U.
      • Hillmer-Vogel U.
      • George A.
      • et al.
      5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo.
      ,
      • Broocks A.
      • Meyer T.
      • Gleiter C.H.
      • Hillmer-Vogel U.
      • George A.
      • Bartmann U.
      • et al.
      Effect of aerobic exercise on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine and to ipsapirone in untrained healthy subjects.
      ), who observed patients with PD/agoraphobia, demonstrated that effective treatment has varying effects on the psychological, neuroendocrinological, and temperature responses to ipsapirone, as it induces cortisol secretion, increases anxiety, and causes other psychopathological symptoms, as well as lowering body temperature. Challenges were performed using ipsapirone and placebo in patients before and after 10 weeks of treatment with clomipramine.
      Serotonin-1A receptor antagonists, such as pindolol, have the capacity to speed up the antidepressant effect of SSRIs by interrupting 5-HT1A autoreceptor inhibition of cell firing that occurs early in the treatment (
      • Artigas F.
      • Perez V.
      • Alvarez E.
      Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors.
      ). There is some promising control data on the role of pindolol augmentation in OCD (
      • Dannon P.N.
      • Sasson Y.
      • Hirschmann S.
      • Iancu I.
      • Grunhaus L.J.
      • Zohar J.
      Pindolol augmentation in treatment-resistant obsessive compulsive disorder: A double-blind placebo controlled trial.
      ). Markovitz et al. (
      • Markovitz P.J.
      • Stagno S.J.
      • Calabrese J.R.
      Buspirone augmentation of fluoxetine in obsessive-compulsive disorder.
      ) reported modest benefits in an open trial on OCD patients in which 9 out of 11 patients reported a beneficial effect.
      Buspirone showed no significant effect in the treatment of PD (
      • Bell C.J.
      • Nutt D.J.
      Serotonin and panic.
      ,
      • Pohl R.
      • Balon R.
      • Yeragani V.K.
      • Gershon S.
      Serotonergic anxiolytics in the treatment of panic disorder: A controlled study with buspirone.
      ,
      • Sheehan D.V.
      • Raj A.B.
      • Sheehan K.H.
      • Soto S.
      Is buspirone effective for panic disorder?.
      ). Ipsapirone, is possibly effective in the treatment of GAD (
      • Cutler N.R.
      • Hesselink J.M.
      • Sramek J.J.
      A phase II multicenter dose-finding, efficacy and safety trial of ipsapirone in outpatients with generalized anxiety disorder.
      ); however, acute administration of ipsapirone causes panic attacks (
      • Broocks A.
      • Meyer T.
      • Opitz M.
      • Bartmann U.
      • Hillmer-Vogel U.
      • George A.
      • et al.
      5-HT1A responsivity in patients with panic disorder before and after treatment with aerobic exercise, clomipramine or placebo.
      ). Lesch (
      • Lesch K.P.
      5-HT1A receptor responsivity in anxiety disorders and depression.
      ) explored the sensitivity of the 5-HT1A receptor in PD and investigated hypothermic, neuroendocrinological, and behavioral responses in 14 patients. Ipsapirone caused hypothermia and adrenocorticotropic hormone (ACTH) release but had only minimal effects on behavior. Panic disorder patients revealed reduced hypothermic and corticoid responses to ipsapirone when compared with control subjects. Hypothermia was expected to reflect presynaptic 5-HT1A receptor activation, while corticoid responses showed activation of postsynaptic 5-HT1A receptors. McDougle et al. (
      • McDougle C.J.
      • Goodman W.K.
      • Leckman J.F.
      • Holzer J.C.
      • Barr L.C.
      • McCance-Katz E.
      • et al.
      Limited therapeutic effect of addition of buspirone in fluvoxamine-refractory obsessive-compulsive disorder.
      ) undertook a placebo-controlled study to subsequently test the efficacy of buspirone in OCD patients. Buspirone was no different from the placebo as a treatment agent. Its role as an augmenting agent in specific refractory cases remains of interest. For further details, see Supplement 1.

       Neuroimaging

       PET Studies on Healthy Volunteers and Anxiety Disorder Patients

      Several positron emission tomography studies on healthy subjects (
      • Tauscher J.
      • Bagby R.M.
      • Javanmard M.
      • Christensen B.K.
      • Kasper S.
      • Kapur S.
      Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: A [(11)C]WAY-100635 PET investigation in healthy volunteers.
      ,
      • Rabiner E.A.
      • Messa C.
      • Sargent P.A.
      • Husted-Kjaer K.
      • Montgomery A.
      • Lawrence A.D.
      • et al.
      A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: Normative data and relationship to methodological, demographic, physiological, and behavioral variables.
      ) and patients with anxiety disorders (
      • Lanzenberger R.R.
      • Mitterhauser M.
      • Spindelegger C.
      • Wadsak W.
      • Klein N.
      • Mien L.K.
      • et al.
      Reduced serotonin-1A receptor binding in social anxiety disorder.
      ,
      • Neumeister A.
      • Bain E.
      • Nugent A.C.
      • Carson R.E.
      • Bonne O.
      • Luckenbaugh D.A.
      • et al.
      Reduced serotonin type 1A receptor binding in panic disorder.
      ) were performed, inspired by the effects found in mice and pharmacological models, showing increased anxious behavior with lower 5-HT1A functioning. Neuroimaging data reveals that reduced 5-HT1A binding is a pathophysiological characteristic of both anxiety and depression and may represent a common neurobiological process in the development of these stress-related disorders. For details on topology of 5-HT1A binding changes and regions of interests, see Table 4.
      Table 4Human PET Studies of Changes in 5-TH1A Receptor Binding Associated with Anxiety Disorders
      Patients/Healthy SubjectsRadiotracerBinding Potential/Distribution VolumeReferences
      PTSD (12/11)[18F]FCWAY= RN, ATPC, PCG, INS, ACC, MTC
      • Bonne O.
      • Bain E.
      • Neumeister A.
      • Nugent A.C.
      • Vythilingam M.
      • Carson R.E.
      • et al.
      No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder.
      SAD (12/18)[11C]WAY-100635 AMY, ACC, INS, RN, MOFC
      • Lanzenberger R.R.
      • Mitterhauser M.
      • Spindelegger C.
      • Wadsak W.
      • Klein N.
      • Mien L.K.
      • et al.
      Reduced serotonin-1A receptor binding in social anxiety disorder.
      PD (16/19)[11C]WAY-100635 RN, AMY, OFC, ALTC (untreated), RN, HIP, AMTC (treated)
      • Nash J.R.
      • Sargent P.A.
      • Rabiner E.A.
      • Hood S.D.
      • Argyropoulos S.V.
      • Potokar J.P.
      • et al.
      Serotonin 5-HT1A receptor binding in people with panic disorder: Positron emission tomography study.
      PD (16/15)[18F]FCWAY ACC, PCG, RN
      • Neumeister A.
      • Bain E.
      • Nugent A.C.
      • Carson R.E.
      • Bonne O.
      • Luckenbaugh D.A.
      • et al.
      Reduced serotonin type 1A receptor binding in panic disorder.
      SAD/PD (0/12)[11C]WAY-100635 HIP, SGC, PCG after 12 weeks SSRI treatment
      • Spindelegger C.
      • Lanzenberger R.
      • Wadsak W.
      • Mien L.K.
      • Stein P.
      • Mitterhauser M.
      • et al.
      Influence of escitalopram treatment on 5-HT(1A) receptor binding in limbic regions in patients with anxiety disorders.
      MDD/PD (28/0)[11C]WAY-100635 TEM, ACC, INS, PHG, HIP in MDD with comorbid PD
      • Sullivan G.M.
      • Oquendo M.A.
      • Simpson N.
      • Van Heertum R.L.
      • Mann J.J.
      • Parsey R.V.
      Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety.
      Healthy Volunteers (0/19)[11C]WAY-100635Negative correlation BP and NEO-PI-R in ACC, PAR, OCC, DLPFC
      • Tauscher J.
      • Bagby R.M.
      • Javanmard M.
      • Christensen B.K.
      • Kasper S.
      • Kapur S.
      Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: A [(11)C]WAY-100635 PET investigation in healthy volunteers.
      Healthy Volunteers (0/61)[11C]WAY-100635No significant correlation of receptor BP with anxiety scores
      • Rabiner E.A.
      • Messa C.
      • Sargent P.A.
      • Husted-Kjaer K.
      • Montgomery A.
      • Lawrence A.D.
      • et al.
      A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: Normative data and relationship to methodological, demographic, physiological, and behavioral variables.
      5-TH1A, serotonin-1A; ↓, significant decrease; =, changes were not significant; ACC, anterior cingulate cortex; ALTC, anterior lateral temporal cortex; AMTC, anterior mediotemporal cortex; AMY, amygdala; ATPC, anterior temporopolar cortex; BP, blood pressure; DLPFC, dorsolateral prefrontal cortex; HIP, hippocampus; INS, insular cortex; MDD, major depressive disorder; MOFC, medial orbitofrontal cortex; MTC, mesiotemporal cortex; NEO-PI-R, Revised NEO Personality Inventory; OCC, occipital cortex; OFC, orbitofrontal cortex; PAR, parietal cortex; PCG, posterior cingulate gyrus; PD, panic disorder; PET, positron emission tomography; PHG, parahippocampal gyrus; PTSD, posttraumatic stress disorder; RN, raphe nuclei; SAD, social anxiety disorder; SGC, subgenual cortex; SSRI, selective serotonin reuptake inhibitor; TEM, temporal cortex.
      The distribution of the 5-HT1A receptor in the human brain (Figure 1) can be quantified using radiolabeled ligands. WAY-100635 is a specific 5-HT1A receptor antagonist that binds with high affinity to the 5-HT1A receptor (
      • Hall H.
      • Lundkvist C.
      • Halldin C.
      • Farde L.
      • Pike V.W.
      • McCarron J.A.
      • et al.
      Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]WAY-100635.
      ,
      • Rabiner E.A.
      • Messa C.
      • Sargent P.A.
      • Husted-Kjaer K.
      • Montgomery A.
      • Lawrence A.D.
      • et al.
      A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: Normative data and relationship to methodological, demographic, physiological, and behavioral variables.
      ,
      • Pike V.W.
      • McCarron J.A.
      • Lammertsma A.A.
      • Osman S.
      • Hume S.P.
      • Sargent P.A.
      • et al.
      Exquisite delineation of 5-HT1A receptors in human brain with PET and [carbonyl-11 C]WAY-100635.
      ). Labeled with the [carbonyl-11C], it can be used safely for quantitative analysis of the binding to 5-HT1A receptors (
      • Farde L.
      • Ito H.
      • Swahn C.G.
      • Pike V.W.
      • Halldin C.
      Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man.
      ,
      • Cliffe I.A.
      A retrospect on the discovery of WAY-100635 and the prospect for improved 5-HT(1A) receptor PET radioligands.
      ,
      • Wadsak W.
      • Mien L.
      • Ettlinger D.
      • Lanzenberger R.
      • Haeusler D.
      • Dudczak R.
      • et al.
      Simple and fully automated preparation of [carbonyl-11C]WAY-100635.
      ).
      Using [carbonyl-11C]WAY-100635 in healthy subjects, a significant negative correlation between 5-HT1A binding potential (BP) and anxiety scores was observed, specifically in the dorsolateral prefrontal, anterior cingulate, parietal, and occipital cortices (
      • Tauscher J.
      • Bagby R.M.
      • Javanmard M.
      • Christensen B.K.
      • Kasper S.
      • Kapur S.
      Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: A [(11)C]WAY-100635 PET investigation in healthy volunteers.
      ). These findings were consistent with results from animal studies showing increased anxiety in mice lacking 5-HT1A receptors (
      • Ramboz S.
      • Oosting R.
      • Amara D.A.
      • Kung H.F.
      • Blier P.
      • Mendelsohn M.
      • et al.
      Serotonin receptor 1A knockout: An animal model of anxiety-related disorder.
      ). This could explain the anxiolytic effect of partial 5-HT1A receptor agonists. However, the results were not replicated by another study in male healthy subjects (
      • Rabiner E.A.
      • Messa C.
      • Sargent P.A.
      • Husted-Kjaer K.
      • Montgomery A.
      • Lawrence A.D.
      • et al.
      A database of [(11)C]WAY-100635 binding to 5-HT(1A) receptors in normal male volunteers: Normative data and relationship to methodological, demographic, physiological, and behavioral variables.
      ).
      Panic disorder was investigated by Neumeister et al. (
      • Neumeister A.
      • Bain E.
      • Nugent A.C.
      • Carson R.E.
      • Bonne O.
      • Luckenbaugh D.A.
      • et al.
      Reduced serotonin type 1A receptor binding in panic disorder.
      ) using the radioligand ((18)F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) and PET. Regions of interest consisted of brain structures with high concentrations of postsynaptic 5-HT1A receptors, i.e., the anterior and posterior cingulate, anterior insular, mesiotemporal, anterior temporopolar cortices, and raphe nuclei. When patients with PD, patients with PD and comorbid depression, and healthy control subjects were compared, it was revealed that distribution volumes did not differ between the two PD groups, while both patient groups differed significantly from control subjects, showing a lower volume of distribution of the radioligand in the anterior cingulate, posterior cingulate cortices, and raphe nuclei. The abnormal function of 5-HT1A receptors appeared to impact specifically on cortical circuitries (anterior and posterior cingulate cortices) that are associated with the regulation of anxiety according to electrophysiological and functional studies in humans, nonhuman primates, and 5-HT1A receptor knockout studies in mice (
      • Gross C.
      • Zhuang X.
      • Stark K.
      • Ramboz S.
      • Oosting R.
      • Kirby L.
      • et al.
      Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.
      ).
      Nash et al. (
      • Nash J.R.
      • Sargent P.A.
      • Rabiner E.A.
      • Hood S.D.
      • Argyropoulos S.V.
      • Potokar J.P.
      • et al.
      Serotonin 5-HT1A receptor binding in people with panic disorder: Positron emission tomography study.
      ) measured 5-HT1A receptor binding in untreated patients after recovery through treatment with SSRIs. Compared with healthy control subjects, in nine PD patients binding was reduced significantly in the raphe nuclei, amygdala, orbitofrontal, and temporal cortices. Recovered patients showed reduced presynaptic binding; however, no significant reduction in postsynaptic binding was observed. This finding is consistent with predictions from studies with knockout mice.
      A study on social anxiety disorder (SAD) was carried out by Lanzenberger et al. (
      • Lanzenberger R.R.
      • Mitterhauser M.
      • Spindelegger C.
      • Wadsak W.
      • Klein N.
      • Mien L.K.
      • et al.
      Reduced serotonin-1A receptor binding in social anxiety disorder.
      ) examining the role of 5-HT1A receptor binding potential in the limbic and paralimbic system, including amygdala, hippocampus, insula, cingulate, and orbitofrontal cortices. These regions were selected because of their central role in the neural processing of fear and anxiety. Using PET and the radioligand [carbonyl-11C]WAY-100635, a group of 12 unmedicated male SAD patients was compared with 18 healthy control subjects. The findings demonstrated a significantly lower 5-HT1A receptor binding potential in SAD patients in the hippocampus (−9.7%), insula (−28.0%), anterior cingulate cortex (−23.8%), amygdala (−21.4%), medial orbitofrontal cortex (−18.4%), and raphe nuclei (−36.4%). After a Bonferroni correction for multiple comparisons, amygdala (p = .024), insula (p = .024), and anterior cingulate cortex (p = .032) remained significant. These results underline the key role of the above brain areas in modulating anxious states.
      Another interesting study by Sullivan et al. (
      • Sullivan G.M.
      • Oquendo M.A.
      • Simpson N.
      • Van Heertum R.L.
      • Mann J.J.
      • Parsey R.V.
      Brain serotonin1A receptor binding in major depression is related to psychic and somatic anxiety.
      ) investigated the association between anxiety scores in major depressive disorder (MDD) and regional 5-HT1A binding. Cortical 5-HT1A binding seems to play a role in the expression of different anxious behaviors occurring in MDD with different relationships to psychic as compared to somatic anxiety. Lower 5-HT1A BP in patients with comorbid PD was associated with higher somatic and lower psychic anxiety. The authors argue that a differentiation between the somatic and psychic components of anxiety may be useful in the development of new therapeutic treatments.
      Although PTSD is commonly comorbid with other anxiety disorders and responds to treatment with SSRIs, patients with PTSD do not show altered 5-HT1A expression (
      • Bonne O.
      • Bain E.
      • Neumeister A.
      • Nugent A.C.
      • Vythilingam M.
      • Carson R.E.
      • et al.
      No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder.
      ).

       Pharmacological Effects on 5-HT1A Receptor Binding

      Positron emission tomography can be used to investigate drug effects on 5-HT1A receptor binding; however, not all neuroimaging studies are in agreement about treatment effects on presynaptic or postsynaptic 5-HT1A receptor binding (
      • Moses-Kolko E.L.
      • Price J.C.
      • Thase M.E.
      • Meltzer C.C.
      • Kupfer D.J.
      • Mathis C.A.
      • et al.
      Measurement of 5-HT1A receptor binding in depressed adults before and after antidepressant drug treatment using positron emission tomography and [11C]WAY-100635.
      ). Several studies suggested that treatment effects of SSRIs might be associated with functional or expression changes in 5-HT1A receptors. This data is in accordance with the BP reduction of 5-HT1A receptors in limbic regions. Sargent et al. (
      • Sargent P.A.
      • Kjaer K.H.
      • Bench C.J.
      • Rabiner E.A.
      • Messa C.
      • Meyer J.
      • et al.
      Brain serotonin1A receptor binding measured by positron emission tomography with [11C]WAY-100635: Effects of depression and antidepressant treatment.
      ) measured a statistically insignificant decrease in BP of 5-HT1A in the raphe nuclei after a 6-week treatment with paroxetine. Furthermore, a continued reduction of the 5-HT1A BP in clinically recovered depressed patients was proposed as a trait variable of depression (
      • Bhagwagar Z.
      • Rabiner E.A.
      • Sargent P.A.
      • Grasby P.M.
      • Cowen P.J.
      Persistent reduction in brain serotonin1A receptor binding in recovered depressed men measured by positron emission tomography with [11C]WAY-100635.
      ). Although these results suggest that 5-HT1A receptors possess a plasticity and reactivity during chronic SSRI treatment, there is still insufficient data available to explain this phenomenon more accurately in patients. According to the transgenic mice models, lower 5-HT1A BP may increase vulnerability toward anxiety disorders. However, one may speculate that the reduction of 5-HT1A receptor binding might also be a compensatory mechanism, especially in the raphe region, within the serotonergic system. This compensatory mechanism may be insufficient in patients lacking further downregulation, therefore further lowering the 5-HT1A receptor binding by treatment may overcome this insufficient compensation. A further possible explanation is that the affinity of 5-HT1A and radioligands may change in the course of some weeks; however, this remains unobserved as only BP (Bmax./KD) has been measured and binding of the frequently used radioligand [carbonyl-11C]WAY-100635 may not be identical to both the high- and low-affinity state of the 5-HT1A receptor. Furthermore, 5-HT1A data measured with [carbonyl-11C]WAY-100635 and based on reference models has to be confirmed by PET studies with arterial blood sampling, given the sometimes contradictory results of these methods.
      A significant decrease in 5-HT1A receptor binding after treatment with escitalopram in patients suffering from anxiety disorders was recently reported by our neuroimaging group (
      • Spindelegger C.
      • Lanzenberger R.
      • Wadsak W.
      • Mien L.K.
      • Stein P.
      • Mitterhauser M.
      • et al.
      Influence of escitalopram treatment on 5-HT(1A) receptor binding in limbic regions in patients with anxiety disorders.
      ). After 12 weeks of treatment, we observed a significant reduction in 5-HT1A receptor binding in the hippocampus (p = .006), subgenual (p = .017), and posterior cingulate (p = .034) cortices, indicating that long-term administration may cause a decrease in the inhibitory modulation of 5-HT on GABAergic and glutaminergic neurons mediated by a reduction of 5-HT1A receptors.

       Genetic Polymorphisms of the 5-HT1A Receptor

      Allelic variations in 5-HT1A receptor expression seem to play an important role in the development and modulation of individual differences in anxiety-related personality traits and anxiety disorders (
      • Lesch K.P.
      • Gutknecht L.
      Focus on the 5-HT1A receptor: Emerging role of a gene regulatory variant in psychopathology and pharmacogenetics.
      ,
      • Lesch K.P.
      Molecular foundation of anxiety disorders.
      ). Results indicate that these polymorphisms also influence therapeutic responses to serotonergic agents. For further details, see Supplement 1.

      Conclusions

      Evidence from preclinical and clinical research, including genetic studies, pharmacological trials, and neuroimaging, reveals a substantial impact of the serotonin system and particularly the 5-HT1A receptor on the neurobiology of anxiety. However, the serotonin system affects and is influenced by many other neurotransmitters in brain structures essential for the processing and expression of anxiety (
      • Coplan J.D.
      • Lydiard R.B.
      Brain circuits in panic disorder.
      ). Animal studies showed modulatory effects of the 5-HT1A receptor on glutamatergic, GABAergic, and dopaminergic neurons, especially in the (pre)frontal cortex and limbic areas (
      • Santana N.
      • Bortolozzi A.
      • Serrats J.
      • Mengod G.
      • Artigas F.
      Expression of serotonin1A and serotonin2A receptors in pyramidal and GABAergic neurons of the rat prefrontal cortex.
      ,
      • Amargos-Bosch M.
      • Bortolozzi A.
      • Puig M.V.
      • Serrats J.
      • Adell A.
      • Celada P.
      • et al.
      Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex.
      ,
      • Puig M.V.
      • Artigas F.
      • Celada P.
      Modulation of the activity of pyramidal neurons in rat prefrontal cortex by raphe stimulation in vivo: Involvement of serotonin and GABA.
      ,
      • Diaz-Mataix L.
      • Scorza M.C.
      • Bortolozzi A.
      • Toth M.
      • Celada P.
      • Artigas F.
      Involvement of 5-HT1A receptors in prefrontal cortex in the modulation of dopaminergic activity: Role in atypical antipsychotic action.
      ). There is a lack of human studies investigating the effects of 5-HT1A receptor activation on other neurotransmitter systems. Future pharmacological functional magnetic resonance imaging (fMRI) studies with 5-HT1A agonists or antagonists will mainly show the effects on the glutamatergic and GABAergic system. However, it must be stressed that for a more comprehensive model supporting the role of the 5-HT1A receptor in anxiety disorders, it will be necessary to include data on other neurotransmitters. As most of the above-mentioned studies draw their conclusions based on animal models, it is necessary to note that it is generally difficult to make inferences on the pathogenesis in humans from preclinical results. Firstly, the periods of increased brain plasticity are clearly different in humans compared to rodents. There are also inherent problems in reproducing the typical stressful experiences of humans in animal tests. Therefore, direct methodological and interspecies comparisons have their limitations. Systematic multimodal studies in primates are necessary to link the findings of 5-HT1A transgenic mice with clinical data more convincingly. Given the lack of knockout models in primates, the effects of 5-HT1A receptor agonists and antagonists should be studied in different developmental periods and may then be combined with quantifications of 5-HT1A receptor binding, using nondisplaceable radioligands and longitudinal molecular neuroimaging. By combining these approaches with the investigations of genetic polymorphisms in the serotonergic system and environmental risk factors, such as stress, a causal model of the influence of 5-HT1A in the etiology of anxiety disorders may be found in primates. It can be stated that anxiety disorders are biologically heterogeneous conditions influenced by genetic, epigenetic, and environmental factors. Therefore, dysregulation of 5-HT1A receptors cannot be considered as the one simple primary factor in anxiety disorders. Possibly, the role of the serotonin system in anxiety disorders is adaptive rather than pathogenic. In the future, a better understanding of 5-HT1A receptor function will provide insight into the origins and improved clinical management of anxiety disorders.
      We especially thank Megan Light for linguistic support, Patrycja Stein, Tobias Gluek, and Markus Savli for editing the manuscript, and Iris Kaiser for administrative support. We are grateful to Wolfgang Wadsak and Markus Mitterhauser for support in positron emission tomography imaging.
      Dr. Kasper has received grant/research support from Eli Lilly, Lundbeck, Bristol-Myers Squibb, GlaxoSmithKline, Organon, Sepracor, and Servier; has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Lundbeck, Pfizer, Organon, Schwabe, Sepracor, Servier, Janssen, and Novartis; and has served on speakers' bureaus for AstraZeneca, Eli Lily, Lundbeck, Schwabe, Sepracor, Servier, and Janssen. Dr. Lanzenberger received a travel grant, research support, and conference speaker honoraria from Lundbeck. Dr. Akimova reports no biomedical financial interests or potential conflicts of interest.

      Supplementary data

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